Phase 2 Study of MLN0128, Combination of MLN0128 With MLN1117, Paclitaxel and Combination of MLN0128 With Paclitaxel in Women With Endometrial Cancer

The primary purpose of this study is to determine if MLN0128 in combination with weekly
paclitaxel improves progression-free survival (PFS) compared to weekly paclitaxel alone.

Eligibility Criteria

Inclusion Criteria:

1. Histologic or cytologic diagnosis of endometrial carcinoma (including endometrioid,
serous, mixed adenocarcinoma, clear-cell carcinoma, or carcinosarcoma).

2. Evidence that the endometrial cancer is advanced, recurrent, or persistent and has
relapsed or is refractory to curative therapy or established treatments.

3. At least 1 prior platinum-based chemotherapeutic regimen, but not more than 2 prior
chemotherapeutic regimens, for management of endometrial carcinoma. Prior treatment
may include chemotherapy, chemotherapy/radiation therapy, and/or
consolidation/maintenance therapy. Chemotherapy administered in conjunction with
primary radiation as a radio-sensitized therapy will be considered a systemic
chemotherapy regimen.

4. Measureable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1,
defined as at least 1 lesion that can be accurately measured in at least 1 dimension
(longest diameter to be recorded). Each lesion must be ≥ 10 mm in long axis when
measured by computed tomography (CT), magnetic resonance imaging (MRI), or caliper
measurement by clinical exam. Lymph nodes must be ≥ 15 mm in short axis when measured
by CT or MRI.

5. Tumor accessible and patient consents to undergo fresh tumor biopsies.

6. Female patients 18 years or older.

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2

8. Female patients who:

- Are postmenopausal for at least 1 year before the screening visit, OR

- Are surgically sterile, OR

- If they are of childbearing potential, agree to practice 1 highly effective
method of contraception and 1 additional effective (barrier) method at the same
time, from the time of signing the informed consent through 90 days (or longer,
as mandated by local labeling [eg, United States Prescribing Information (USPI),
Summary of Product Characteristics (SmPC), etc.]) after the last dose of study
drug, OR

- Agree to practice true abstinence, when this is in line with the preferred and
usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation,
symptothermal, postovulation methods], withdrawal, spermicides only, and
lactational amenorrhea are not acceptable methods of contraception. Female and
male condoms should not be used together.)

9. Clinical laboratory values as specified below within 4 weeks before the first dose of
study drug:

- Bone marrow reserve consistent with absolute neutrophil count (ANC) ≥ 1500/μL;
platelet count ≥ 100,000/μL; hemoglobin A1c (HbA1c) < 6.5%.

- Total bilirubin must be ≤ 1.5 x the upper limit of normal (ULN).

- Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) must be ≤ 2.5
x the upper limit of the normal range. AST and ALT may be elevated up to 5 times
the ULN if their elevation can be reasonably ascribed to the presence of
metastatic disease in liver.

- Creatinine clearance ≥ 50 mL/min/1.73 m^2 based either on Cockcroft-Gault
estimate or based on a 12- or 24-hour urine collection.

- Fasting serum glucose < 130 mg/dL and fasting triglycerides ≤ 300 mg/dL.

10. Ability to swallow oral medications, willingness to perform mucositis prophylaxis,
and suitable venous access for the study-required blood sampling.

11. Voluntary written consent must be given before performance of any study-related
procedure not part of standard medical care, with the understanding that consent may
be withdrawn by the patient at any time without prejudice to future medical care.

Exclusion Criteria:

1. Previous treatment with any weekly taxane regimen.

2. Previous treatment with phosphoinositide 3-kinase (PI3K), serine/threonine-specific
protein kinase (AKT), dual PI3K/ mammalian (or mechanistic) target of rapamycin
(mTOR) inhibitors, target of rapamycin complex 1/2 (TORC1/2) inhibitors or TORC1
inhibitors.

3. Treatment with strong inhibitors and/or inducers of cytochrome P450 3A4 (CYP3A4),
CYP2C9, or CYP2C19 within 1 week preceding the first dose of study drug.

4. Initiation of treatment with hematopoietic growth factors, transfusions of blood and
blood products, or systemic corticosteroids (either intravenous (IV) or oral
steroids, excluding inhalers) within 1 week before administration of the first dose
of study drug (patients already receiving erythropoietin on a chronic basis for ≥ 4
weeks are eligible).

5. Is taking proton pump inhibitors (PPIs) within 7 days of the first dose of study drug
or who require treatment with PPIs throughout the trial or those who are taking H2
receptor antagonists within 24 hours of the first dose of study drug.

6. A prothrombin time (PT) or activated partial thromboplastin time (aPTT) above the ULN
or a history of a coagulopathy or bleeding disorder.

7. Sensory or motor neuropathy ≥ Grade 2.

8. Central nervous system (CNS) metastasis, endometrial leiomyosarcoma, or endometrial
stromal sarcoma.

9. Manifestations of malabsorption due to prior gastrointestinal surgery,
gastrointestinal disease, or for some other reason that may alter the absorption of
MLN0128 or MLN1117. In addition, patients with enteric stomata are also excluded.

10. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease,
active CNS disease, active infection, or any other condition that could compromise
participation of the patient in the study.

11. Known human immunodeficiency virus infection.

12. History of any of the following within the last 6 months before administration of the
first dose of study drug:

- Ischemic myocardial event, including angina requiring therapy and artery
revascularization procedures.

- Ischemic cerebrovascular event, including transient ischemic attack and artery
revascularization procedures.

- Requirement for inotropic support (excluding digoxin) or serious (uncontrolled)
cardiac arrhythmia (including atrial flutter/fibrillation, ventricular
fibrillation, or ventricular tachycardia).

- Placement of a pacemaker for control of rhythm.

- New York Heart Association Class III or IV heart failure.

- Pulmonary embolism.

13. Significant active cardiovascular or pulmonary disease before administration of the
first dose of study drug, including:

- Uncontrolled hypertension (ie, either systolic blood pressure > 180 mm Hg or
diastolic blood pressure > 95 mm Hg).

- Pulmonary hypertension.

- Uncontrolled asthma or oxygen saturation < 90% by arterial blood gas analysis or
pulse oximetry on room air.

- Significant valvular disease; severe regurgitation or stenosis by imaging
independent of symptom control with medical intervention; or history of valve
replacement.

- Medically significant (symptomatic) bradycardia.

- History of arrhythmia requiring an implantable cardiac defibrillator.

- Baseline prolongation of the rate-corrected QT interval (QTc; eg, repeated
demonstration of QTc interval > 480 ms, or history of congenital long QT
syndrome, or torsades de pointes).

14. Diagnosed or treated for another malignancy within 2 years before administration of
the first dose of study drug or previously diagnosed with another malignancy and have
any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma
in situ of any type are not excluded if they have undergone complete resection.

Principal Investigator

Medical Monitor

Study Contact

Takeda Study Registration Call Center, GlobalOncologyMedinfo@takeda.com, +1-866-835-2233

Estimated Completion Date

Friday, August 31, 2018

ClinicalTrials.gov #

NCT02725268
05/11/2017